Download Progastrin-releasing peptide – a useful and reliable

Translated from the original German:
Holdenrieder/Pawel – Progastrin-releasing peptide
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Medicine Section
Progastrin-releasing peptide – a useful and reliable biomarker in
small cell lung cancer
Stefan Holdenrieder, Joachim von Pawel
Abstract
In the last few years the biomarker progastrin-releasing peptide (ProGRP) has
proved a useful and reliable laboratory parameter for differential diagnosis and
treatment management of lung cancer. ProGRP displays high sensitivity and
specificity for small cell lung cancer (SCLC) and is suitable for differentiating it
from benign lung disease, lung cancer of non-small cell histology (NSCLC) and
metastatic non-lung cancers. This distinction is of considerable practical relevance
in view of the different treatment approaches in SCLC and NSCLC. Differential
diagnostic classification of indeterminate pulmonary nodules can be further
improved by combined use of a lung marker panel comprising ProGRP, NSE,
CYFRA 21-1, CEA and SCCA. Serial ProGRP measurement during treatment and
follow-up of SCLC provides important information about therapeutic response or
tumour progression.
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Holdenrieder/Pawel – Progastrin-releasing peptide
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Lung cancer – a medical and social challenge
Lung cancer remains a formidable medical and health policy challenge. In Germany
alone about 50,000 people a year develop lung cancer and over 42,000 die of it (1).
With 1.35 million new cases and almost 1.2 million deaths a year, it is one of the
most dangerous cancers worldwide (2). The close link between lung cancer and
smoking is widely acknowledged and has prompted numerous anti-smoking
campaigns.
One reason for the high mortality rate is the frequently late diagnosis of lung cancer.
Symptoms often appear only at an advanced tumour stage, when therapeutic
options are limited. Over 70% of lung cancers are not amenable to complete surgical
removal and require systemic chemotherapy or radiotherapy (3-5). n addition, the
treatment approach is quite different in different histological subgroups. While
primary tumour resection is the primary goal for the common non-small cell subtype
(NSCLC, approx. 80%), which includes adenocarcinoma and squamous cell
carcinoma, this is not normally useful for the small cell subtype (SCLC, approx. 20%)
owing to the tumour’s pattern of growth and spread. On the other hand, the
malignant cells in the latter case respond very well to cytotoxic chemotherapy or
radiotherapy, although the remissions thus achieved generally last for only a limited
time before further tumour progression (3-5).
Diagnostic requirements
The significance of this for medical diagnostics is that in addition to the assessment
of suspicious clinical and imaging signs of cancer, histological classification of a
tissue sample is essential for further treatment planning. Although an unequivocal
and accurate diagnosis is possible in many cases, there are often difficulties, for
example if a high-quality biopsy cannot be taken or if different histopathological cell
types are found within one tumour or in the presence of metastases. In these
situations additional diagnostic tools can contribute to more reliable classification.
A special role is played by biomarkers detectable in the blood, which sensitively
reflect biochemical changes of malignancy. The test methods available today are
generally highly sensitive, inexpensive, robust, readily reproducible and quick to
perform, delivering quantitative results that undergo continuous quality control.
Whether individually or as panels of multiple markers, these so-called “tumour
markers” provide important information for differential diagnosis and prognostic
evaluation before planned cancer treatment (6,7). It is important to bear in mind that
the release of these markers into the bloodstream can vary according to tumour size
or aggressiveness, so that very small or slow-growing tumours sometimes remain
undetected (limited sensitivity), while in some cases slightly raised levels are also
found in non-malignant disease (limited specificity). Despite these known limitations,
“tumour marker” release patterns in particular are often very helpful in classifying
equivocal findings (6,7).
The “tumour marker” constellation of cytokeratin-19 fragments (CYFRA 21-1),
carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCA),
neurone-specific enolase (NSE) and progastrin-releasing peptide (ProGRP) can be
used in this way for differential diagnosis of a suspicious pulmonary nodule. In most
cases this can distinguish between lung cancer and benign lung disease or non-lung
cancer metastases (8). The expression and release pattern also often allows
conclusions to be drawn about the underlying histology: Predominant expression of
CYFRA 21-1 and CEA suggests non-small cell lung cancer, while strong SCCA
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expression indicates squamous cell carcinoma. By contrast, marked release of
ProGRP and/or NSE indicates with high probability the presence of small cell lung
cancer (6-8).
Progastrin-releasing peptide (ProGRP) as a biomarker for small cell lung
cancer
ProGRP is the precursor of gastrin-releasing peptide (GRP). This corresponds in
mammals to the bombesin of amphibians, which has been used for years for
histopathological classification of lung tissues. Because of the instability of GRP in
blood, the more stable recombinant ProGRP [31-98] was developed as a serum
marker. ProGRP consists of 125 amino acids; there are three different ProGRP
isoforms with a common amino terminus and variable carboxy termini. GRP is
thought to act as a neurotransmitter in the human nervous system and is also found
in neuroendocrine cells of the gastrointestinal and respiratory tracts (6-8).
The ProGRP biomarker is released in particular by small cell lung cancer (SCLC)
cells and is often already clearly raised in the serum of patients with a localised
tumour (limited disease). Very high ProGRP concentrations have also been reported
in the blood of patients with very rare medullary thyroid cancer. By contrast, it is not
released to an appreciable extent in non-small cell lung cancer (NSCLC), other
cancers or benign lung disease. These properties make ProGRP a highly sensitive
and specific biomarker for SCLC (6,9,10).
For diagnostic classification of moderately raised ProGRP levels it is important to
bear in mind that impaired renal function can lead in some cases to ProGRP blood
concentrations up to about 300 pg/mL (6,11,12). In benign gastrointestinal or
respiratory tract disease, on the other hand, only slightly elevated levels are
occasionally observed (6,12). The 95th percentile for healthy subjects is 40-60
pg/mL, depending on the test employed. For some ProGRP tests better stability has
been found in plasma than in serum (13), although in our experience this is not true
of all tests.
ProGRP in the differential diagnosis of small cell lung cancer
In combination with CYFRA 21-1, CEA, SCCA and NSE, marked ProGRP and/or
NSE release in the absence of SCCA release indicates with high probability the
presence of small cell lung cancer. In particular, ProGRP levels above 300 pg/mL
can be regarded as virtually diagnostic criteria, assuming normal renal function. In a
large study, benign lung disease and lung metastases from other cancers showed
merely levels below 100 pg/mL. With few exceptions – possibly due to tumours of
mixed histology – ProGRP levels in NSCLC were below 300 pg/mL (8). At 95%
specificity versus benign lung disease, diagnostic sensitivity in various studies
ranged from 47 to 80% (10,14,15), exceeding that of NSE. Because of the different
biological backgrounds of the two markers, ProGRP and NSE had additive
sensitivity, meaning that use of both markers results in enhanced diagnostic
accuracy (8,10,14).
ProGRP and NSE are also the two key markers for distinguishing between SCLC
and NSCLC. In combinations with the other lung markers a sensitivity of over 80%
was achievable at a specificity of 95% (8). As already mentioned, this classification is
particularly important when planning further treatment steps (5).
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ProGRP in the treatment management of small cell lung cancer
Several questions are relevant to treatment management:
1. Can ProGRP predict the patient’s response to planned therapy and/or
prognosis before the start of treatment?
2. Do ProGRP kinetics during cytotoxic therapy permit reliable monitoring of
treatment response or early detection of non-response?
3. Do ProGRP kinetics in the follow-up – i.e. post-treatment – setting permit
early and reliable detection of cancer recurrence or progression?
Few studies have so far been conducted on these questions. No reliable evidence
has yet been found that pretherapeutic ProGRP levels are of prognostic and/or
predictive value (17-20). This is also consistent with observations of high ProGRP
levels both in prognostically favourable early tumour stages and in advanced stages
(8,14,16).
As with most tumour markers, continuously and strongly decreasing ProGRP levels
during cytotoxic therapy are indicative of a good response, while constant or rising
levels suggest poor treatment efficacy or tumour progression (20,21). It is noteworthy
that ProGRP levels fall markedly during treatment in most patients, even those
experiencing progression. The groups with absent (or only brief) response and
subsequent progression are distinguishable at most by a somewhat smaller
decrease, quickly followed by a renewed increase (22). Figure
In a further study the response to treatment was evident from changes in ProGRP
levels after only two cycles of chemotherapy – and more clearly so than with NSE.
Moreover, these ProGRP kinetics had prognostic value for one-year patient survival
(23). These results accord with our own experience, which likewise shows a high
association between ProGRP levels after one and two cycles of first-line
chemotherapy and therapeutic response. Combination with the markers NSE and
CYFRA 21-1 further enhanced its value for biochemical staging (at the time of
radiological follow-up after the second cycle). For early assessment of treatment
response (after only one cycle), combination with the marker nucleosomes resulted
in further enhancement (20).
Although these studies already suggest great potential for ProGRP for monitoring
treatment in SCLC patients, further studies will be needed to define the ideal
intervals for ProGRP determination and cutoff values or algorithms for assessing
marker changes. On this basis ProGRP can then be deployed – perhaps in
combination with other markers – in future treatment management strategies.
Conclusions
The new biomarker progastrin-releasing peptide (ProGRP) represents an informative
and reliable laboratory parameter for small cell lung cancer. In combination with the
tumour markers CYFRA 21-1, CEA, SCCA and NSE it enables sensitive and specific
differential diagnosis of suspicious pulmonary nodules. Serial measurement of
ProGRP permits early assessment of response to cytotoxic therapy or of tumour
progression in SCLC. However, clinical influencing factors such as renal impairment
should be taken into account when interpreting ProGRP results.
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Figure legend
ProGRP, NSE and CYFRA 21-1 time courses in a patient with small cell lung cancer
during and after combined first-line chemotherapy (CTx1) and radiotherapy (RTx)
and sustained complete remission. ProGRP levels showed a rapid, complete and
lasting fall to within the range of individual baseline values.
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Figure legend
ProGRP, NSE and CYFRA 21-1 time courses in a patient with small cell lung cancer
during first-line chemotherapy (CTx1). While partial remission was initially achieved,
this was followed by tumour progression. ProGRP levels showed an initial marked
fall, but soon began to rise again continuously.
Translated from the original German:
Holdenrieder/Pawel – Progastrin-releasing peptide
Addresses for correspondence:
Stefan Holdenrieder MD
Institute of Clinical Chemistry and Clinical Pharmacology
Bonn University Hospital
Sigmund-Freud Str. 25
53105 Bonn
Germany
Tel: +49 228 287 12126
Fax: +49 228 287 12159
Email: [email protected]
Joachim von Pawel MD
Department of Oncology
Asklepios Hospital Munich-Gauting
Robert-Koch-Allee 2
82131 Gauting
Germany
Tel: +49 89 85791 2101
Fax: +49 89 85791 2106
Email: [email protected]
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